Title

Author

Defense Date

1977

Document Type

Thesis

Degree Name

Doctor of Philosophy

Department

Pharmacology & Toxicology

First Advisor

Raymond Bath

Abstract

The effects of ethanol administration on the antinociceptive activity, lethal properties and brain concentration of methadone, were investigated. The effect of ethanol on the antinociceptive activity of methadone was assessed by the hot-plate and tail-flick tests. Concentrations of methadone in the brain were determined by the use of 3H-methadone as well as by gas liquid chromatographic analysis. The study showed that moderate doses of ethanol did not alter tail-flick or hot-plate response by themselves. However, when combined with methadone, ethanol produced a significant increase in the antinociceptive effectiveness of methadone as measured by both a decrease in the ED50 of methadone and by an increased intensity and prolonged duration of methadone antinociception. Ethanol increased the antinociceptive activity of methadone in both naive and methadone-tolerant mice. This increased activity was not due to simple addition of subthreshold effects of ethanol nor was it due to an ethanol-mediated increase in whole brain·concentrations of methadone. It is hypothesized that the increased antinociceptive activity was the result of an ethanol-mediated increase in central nervous system sensitivity to the antinociceptive activity of methadone.

Ethanol pretreatment produced significantly lower brain concentrations of methadone compared to controls when methadone was administered subcutaneously. When both drugs were administered orally, ethanol administration resulted in brain concentrations of methadone initially less than control and at later times greater than control. In both ethanol and water-pretreated mice there was an excellent correlation between the whole brain concentration of methadone and antinociceptive effect, but the antinociceptive effect at any brain concentration of methadone was greater in ethanol-pretreated mice. Although ethanol produced significant alterations in the brain concentration of methadone, the brain concentration of ethanol was generally not altered by methadone administration. Investigations of the excretion of methadone and its metabolites and the half-life of methadone in the brain failed to reveal any significant ethanol-induced alterations.

A dose of ethanol which increased the antinociceptive activity of methadone did not alter the oral or subcutaneous LD50 of methadone, although mice that died as a result of ethanol and methadone administration died at lower whole brain concentrations of methadone than those that died as a result of methadone alone. The LD50 of ethanol was significantly decreased in mice maintained on a methadone dose of 100 mg/kg/day.